Cerebrospinal Fluid Biomarkers of Simian Immunodeficiency Virus Encephalitis

Abstract

Antiretroviral therapy has led to increased survival of HIV-infected patients but also increased prevalence of HIV-associated neurocognitive disorders. We previously identified YKL40 as a potential cerebrospinal fluid (CSF) biomarker of lentiviral central nervous system (CNS) disease in HIV-infected patients and in the macaque model of HIV encephalitis. The aim of this study was to define the specificity and sensitivity along with the predictive value of YKL40 as a biomarker of encephalitis and to assess its relationship to CSF viral load. CSF YKL40 and SIV RNA concentrations were analyzed over the course of infection in 19 SIV-infected pigtailed macaques and statistical analyses were performed to evaluate the relationship to encephalitis. Using these relationships, CSF alterations of 31 neuroimmune markers were studied pre-infection, during acute and asymptomatic infection, at the onset of encephalitis, and at necropsy. YKL40 CSF concentrations above 1122 ng/ml were found to be a specific and sensitive biomarker for the presence of encephalitis and were highly correlated with CSF viral load. Macaques that developed encephalitis had evidence of chronic CNS immune activation during early, asymptomatic, and end stages of infection. At the onset of encephalitis, CSF demonstrated a rise of neuroimmune markers associated with macrophage recruitment, activation and interferon response. CSF YKL40 concentration and viral load are valuable biomarkers to define the onset of encephalitis. Chronic CNS immune activation precedes the development of encephalitis while some responses suggest protection from CNS lentiviral disease.

CSF Inflammation Markers Associated with Asymptomatic Viral Escape in Cerebrospinal Fluid of HIV-Positive Individuals on Antiretroviral Therapy

“…Although CSF NFL, GFAP, and YKL-40 levels were not significantly different between PWH with or without asymptomatic CSF viral escape, CSF YKL-40 correlated positively with CSF IL-1β, IFN-γ, IP-10, and NFL and negatively with neurocognitive T scores. Previous studies have suggested that CSF YKL-40 is associated with increased plasma and CSF HIV/SIV RNA, HIV/SIV encephalitis, and markers of axonal injury [ 19 , 21 , 22 , 48 , 51 , 52 ]. CSF YKL-40 is a biomarker of glial activation associated with neuroinflammation [ 19 , 21 , 53 ] that is produced by CNS macrophages, microglia, and astrocytes.…”

The Role of Adipokines in the Pathologies of the Central Nervous System

“…This suggests the potential utility of CSF YKL-40 as a predictive marker for encephalitis, as retrospective analysis of serial CSF samples revealed a YKL-40 increase occurring two to eight weeks prior to the manifestation of clinical symptoms in affected animals. Moreover, it is believed that the initiation of YKL-40 production within the central nervous system (CNS) occurs in astrocytes [77]. In another study involving BRP-39-deficient mice, these animals exhibited more severe clinical scores in experimental autoimmune encephalitis (EAE) and displayed heightened neuroinflammation and gliosis compared to their wild-type counterparts.…”

Advances in SIV/SHIV Non-Human Primate Models of NeuroAIDS

“…Thus, CSF neopterin is considered a very specific biomarker of inflammation in the CNS compared to the periphery. Another marker of CSF neuronal damage is human cartilage glycoprotein 39 (YKL-40) produced by microglia following SIV infection [ 72 , 73 , 74 ]. YKL-40 is upregulated in the CSF of SIV-infected pigtailed macaques that develop encephalitis and correlates with an increase of viral load in CSF [ 74 ], while macaques that do not develop encephalitis maintain consistent baseline levels of CSF YKL-40 throughout the course of infection.…”

“…Another marker of CSF neuronal damage is human cartilage glycoprotein 39 (YKL-40) produced by microglia following SIV infection [ 72 , 73 , 74 ]. YKL-40 is upregulated in the CSF of SIV-infected pigtailed macaques that develop encephalitis and correlates with an increase of viral load in CSF [ 74 ], while macaques that do not develop encephalitis maintain consistent baseline levels of CSF YKL-40 throughout the course of infection. Neurofilament light chain (NF-L) drastically increases in CNS during asymptomatic and chronic stages of infection in animals that develop encephalitis, and drops in animals that do not [ 70 ], showing increased neuroaxonal damage in animals that develop encephalitis.…”